To date, in cancer (malignant tumor) treatment, surgery, irradiation or chemotherapy is used alone or in any combination thereof as required. Among them, anti-cancer agents (anti-malignant-tumor agents) used in the chemotherapy inherently have cytotoxicity and damage not only the cancer cells but also human normal cells to cause side effects. Thus, it is important that the anti-cancer agents are administered to patients so as to prevent or treat such side effects as far as possible and to provide sufficient anti-cancer effects.
Examples of the side effects induced by administration of anti-cancer agents include variously blood disorders, gastrointestinal disorders, nerve disorders, etc. and, in particular, acute or chronic nerve disorders have increased as a recent trend. This trend is considered to be caused by the following factors: frequent occurrence of nerve disorders as a main side effect of new anti-cancer agents providing remarkable anticancer effects, the effects of multiple drug therapy as recent main therapy, and a relatively improved tendency of side effects such as blood disorders and gastrointestinal disorders. In this manner, no effective countermeasures against the nerve disorders, which are a main side effect caused by the current cancer chemotherapy, are available once the disorders have developed, due to the difficulty of nerve cell regeneration. Therefore, serious symptoms or irreversible disorders may be developed so that the administration of anti-cancer agents cannot be continued in some cases. Accordingly, the nerve disorders are an important therapeutic problem for cancer.
The nerve disorders induced by administration of anti-cancer agents are observed in, besides the central nervous system, the autonomic nervous system, and the peripheral nervous system, the sense organs such as the sense of taste. Among them, nerve disorders in the peripheral nervous system that occur in a comparatively high frequency to be problems are pains such as a stinging pain and burning pain, paresthesia such as numbness of limb extremities and a burning sensation, hyperesthesia such as hypersensitivity to cold stimuli, dysesthesia such as sensory loss, sensory paralysis and sense of discomfort, sensory ataxia, muscle weakness or the like. In the present invention the anti-cancer agent inducing the peripheral nerve disorder may be any kinds of them, and the lesions in the peripheral nervous system induced by administration of anti-cancer agents are considered to be mainly due to neuroaxonal degeneration. Microtubules in the axon play an important role in maintaining the normal function of cells, for example, forming a spindle during cell division, and involving in placing the subcellular organelle and transporting substances. A taxane drug such as paclitaxel and docetaxel and a vinca alkaloid drug such as vincristine, vinblastine, vindesine and vinorelbine target the microtubules to inhibit the proliferation of cancer cells. Thus, it is considered that the microtubules in normal nerve cells are also more likely to be damaged to cause nerve disorders. Furthermore, it is considered that a platinum drug such as oxaliplatin, carboplatin, cisplatin and nedaplatin directly damage nerve cells, and consequently secondarily leading to axonopathy, so that it is considered to cause much of the nerve disorders.
In spite of the above situation, the neurotoxicity of the anti-cancer agents has not been studied in detail and sufficient prophylactic and therapeutic methods for the peripheral nerve disorder which is a side effect caused by taxane anti-cancer drugs, etc. as described above have yet to be established. Therefore, at present, for relieving numbness symptoms, vitamin B12 preparations such as mecobalamin and a Chinese herbal medicine, Gosha-jinki-gan, are used. For pains, an antidepressant (amitriptyline hydrochloride), an antiepileptic agent (carbamazepine), an antiarrhythmic agent (mexiletine hydrochloride), adrenocorticosteroid and the like are used. However, these therapies have limited effectiveness. Stopping the administration of anti-cancer agent is the only reliable method for preventing the development of the peripheral nerve disorder, but even after stopping the administration, the peripheral nerve disorder may continue or get worse. It would require the administration of anti-cancer agents for treatment of cancer, but a significant peripheral nerve disorder can make it difficult to continue the administration of important anti-cancer agents which are highly effective against cancer and it becomes a serious problem for treatment of cancer. In view of the above problems, more effective prophylactic or therapeutic agents against a peripheral nerve disorder induced by anti-cancer agents have been strongly required in clinical practices.
In addition, a nerve cell is a cell having an information transmitting function, and its damage emerges as a serious loss of a cranial nerve function. The regeneration of the axon can hardly be expected in central nerves of the brain and the spinal cords, and thus, when nerve cells are found to have damages or degeneration, it is necessary to protect and activate the nerve cells. As the biological protective mechanism mentioned above, the roles of neurotrophic factors in differentiation of nerve cells, survival sustenance, increase in synapse functions, and regeneration or repair of the damaged nerve axon are indispensable.
Among neurotrophic factors, a nervous growth factor (NGF), a brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), and the like construct a neurotrophin family having 50% or more of sequence homology with NGF as a prototype. When the extracellularly secreted neurotrophin is bound to high-affinity receptor (Trks) on a nerve cell membrane, signals are transmitted in three directions in the nerve cells. A transcription factor CREB (cAMP-response element binding protein) is activated through the activation of MAP kinase (mitogen-activated protein (MAP) kinases/extracellular signal-regulated protein kinases 1/2 (ERK1/2)) information transmission pathway, including the activation (phosphorylation) of the MAP kinase, which is one of the high-affinity receptors, thereby regulating numerous gene expressions. Therefore, once signal transmissions through a MAP kinase information transmission pathway can be activated, there is a possibility of clinical applications to a nervous disorder caused by degeneration of nerve cells or cellular death. Further, there is a report about associations between BDNF and some diseases.
According to the studies on gene polymorphisms of BDNF, it is reported that particular polymorphisms of the BDNF are associated with Parkinson's disease, Alzheimer's disease, depression, bipolar depression, anxiety disorders, autistic disorder spectrum, glaucoma, and the like. Furthermore, there are some reports that decrease in a synapse function of a genetically converted mouse having Huntington's disease is cured with administration of a BDNF, and that administration of a MAP kinase phosphorylation inhibitor provokes an antidepressant condition.
Neurotrophic factors, as is seen in examples of BDNF mentioned above, show therapeutic effects against particular nerve diseases, and have some actions of germinating the axon and extending its length. However, since neurotrophic factors are high-molecular weight proteins, they have a problem of having difficulty in reaching the brain since they cannot pass through a blood-brain barrier even if administered from a peripheral. Thus, it has been tried to search for a pharmaceutical agent having a neurotrophic factor-like activity that activates nerve cells with a low-molecular weight compound and a pharmaceutical agent promoting the production and secretion of neurotrophic factors.
Patent Publication 1 discloses that a fatty acid or a fatty acid ester having 8 carbon atoms or 10 to 12 carbon atoms has a neutrophic factor-like activity. However, the compounds described in Patent Publication 1 is an ordinary fatty acid or an ester thereof, clearly differing in the structure in the carboxylic acid moiety from the compounds of the present invention. In addition, the compounds of the present invention, 1-((E)-2-decenoyl)pyrrolidine (Compound 1), 1-((E)-2-decenoyl)piperidine (Compound 5) and 1-((E)-2-decenoyl)azepane (Compound 32), are disclosed in Patent Publication 2, and the compound of the present invention, (4-((E)-2-decenoyl) morpholine (Compound 17), is disclosed in Patent Publication 3 or Non-Patent Publication 1, respectively. However, Patent Publication 2 relates to a toxic action against molluskans, and Patent Publication 3 relates to growth inhibitory actions against disease germs or molds, and Non-Patent Publication 1 is a publication relating to a repellant against houseflies. In conclusion, none of these publications include pharmaceutical applications of the compounds of the present invention and any descriptions suggesting the applications.